Richard Frenette

Biaryl synthesis via suzuki coupling on a solid support

Abstract Aryl boronic acids undergo a facile and efficient palladium catalyzed cross-coupling reaction with aryl bromides and iodides that are bound to a Merrifield resin. Simple transesterification releases the biaryl products from the solid support in excellent purity and yield.

Rhodium acetate catalyzes the addition of carbenoids α- to ether oxygens

Abstract Diazo-carbonyl compounds, when catalzed by rhodium acetate, insert preferentially adjacent to ether oxygens. This phenomenon was exploited to develop a synthesis of 3(2H)-furanones.

Discovery of disubstituted phenanthrene imidazoles as potent, selective and orally active mPGES-1 inhibitors

Phenanthrene imidazoles 26 and 44 have been identified as novel potent, selective and orally active mPGES-1 inhibitors. These inhibitors are significantly more potent than the previously reported chlorophenanthrene imidazole 1 (MF63) with a human whole blood IC50 of 0.20 and 0.14 microM, respectively. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model at oral doses as low as 14 mg/kg. Both active and selective mPGES-1 inhibitors (26 and 44) have a relatively distinct pharmacokinetic profile and are suitable for clinical development.

Stereoselective synthesis of endo-1,3 dimethyl-2,9 dioxabicyclo[3-3.1] nonane

Abstract The title compound was synthesized using a novel approach to form a [3.2.1] oxabicyclic ring system. This was achieved through an intramolecular CH insertion of a carbenoid intermediate.

NOVEL 1,2-DIARYLCYCLOBUTENES : SELECTIVE AND ORALLY ACTIVE COX-2 INHIBITORS

A series of novel 2,3-diaryl-2-cyclobuten-l-ones have been synthesized and have been evaluated with respect to their ability to inhibit the isozymes of cyclooxygenase, COX-1 and COX-2. 4,4-Dimethyl-2- phenyl-3-(4-(methylsulfonyl)phenyl)cyclobutenone 22 was found to be highly selective for inhibition of COX-2 and was orally active (EDs0 = 2.4 mg/kg) in the rat paw edema model. Copyright

Synthesis of β-Trimethylsilyloxythioethers and β-Hydroxythioethers by the Reaction of Epoxides with Aryl- and Alkylthiotrimethylsilanes

Abstract As part of our research into methods for the synthesis of leukotrienes (LTC4, LTD4, and LTE4)1, important natural mediators of allergic asthma, we have sought to develop mild and stereo-selective procedures for the preparation of complex β-hydroxythio-ethers. We have recently described the reaction of the S-trimethylsilyl derivative of N-trifluoroacetylglutathione dimethyl ester with the highly reactive epoxide, leukotriene A4, as a key step in the synthesis of LTC4 2. We now wish to report on the general synthetic utility and some mechanistic aspects of this novel reaction.

The discovery of a new structural class of potent orally active leukotriene D4 antagonists

Abstract A new, potent, orally active leukotriene D 4 receptor antagonist has been discovered. The structure -activity relationship leading to L-695,499 is described.

Substituted 4-(2,2-diphenylethyl)pyridine-N-oxides as phosphodiesterase-4 inhibitors: SAR study directed toward the improvement of pharmacokinetic parameters

A detailed SAR study directed toward the optimization of pharmacokinetic parameters for analogues of L-791,943 is reported. The introduction of a soft metabolic site on this structure permitted the identification of L-826,141 as a potent phosphodiesterase type 4 (PDE4) inhibitor that is well absorbed and that presents a shorter half-life than L-791,943 in a variety of animal species. The efficacy of L-826,141 is also demonstrated in different in vivo models.

Substituted indoles as potent and orally active 5-lipoxygenase activating protein (FLAP) inhibitors

This paper reports on the SAR investigation of inhibitors of 5-lipoxygenase activating protein (FLAP) based on MK-0591. Emphasis was made on modifications to the nature of the link between the indole and the quinoline moieties, to the substitution pattern around the two heterocycles and to possible replacements of the quinoline moiety. Lead optimization culminated in (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(pyridin-2-ylmethoxy)-ind ol-2-yl]-2,2-dimethylpropanoic acid (18k), as a potent inhibitor of leukotriene biosynthesis that is well absorbed and active in functional models.

Peripheral Phosphodiesterase 4 Inhibition Produced by 4-[2-(3,4-Bis-difluoromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl]-3-methylpyridine-1-oxide (L-826,141) Prevents Experimental Autoimmune Encephalomyelitis

Administration of phosphodiesterase 4 (PDE4) inhibitors suppresses the pathogenesis associated with experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In the present study, we compared the effects of rolipram and 4-[2-(3,4-bis-difluoromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl]-3-methylpyridine-1-oxide (L-826,141), a novel nonbrain penetrant PDE4 inhibitor, on the onset and severity of clinical signs in a chronic, nonrelapsing/remitting model of EAE. Both rolipram (10 mg/kg p.o.) and L-826,141 (3 mg/kg p.o.) reduced the severity of EAE relative to controls, whereas L-826,141 (3 mg/kg p.o.) also delayed disease onset. To assess whether L-826,141 prevented EAE progression after the first signs of clinical onset, rolipram (10 mg/kg p.o.) or L-826,141 (3 or 30 mg/kg p.o.) were administered 24 h after the first signs of EAE were observed. Only L-826,141 at a dose of 30 mg/kg p.o. significantly decreased the clinical severity of EAE compared with vehicle controls. Immunohistochemical detection of the neuronal activity marker Fos confirmed that L-826,141 did not reach concentrations in the central nervous system sufficient to activate central neurons. Lipopolysaccharide-induced tumor necrosis factor-α in whole blood and plasma concentrations of L-826,141 revealed that only the 30-mg/kg dose resulted in levels sufficient to produce a near complete inhibition of PDE4 activity in immune cells. Taken together, these results demonstrate that peripheral PDE4 inhibition, produced by L-826,141, prevents the progression of EAE after the first onset of clinical signs, and suggest that similar compounds may have clinical efficacy in the treatment of MS.